Genetic and Clinical Characteristics of Patients in the Middle East With Multisystem Inflammatory Syndrome in Children
Authors: Walid Abuhammour, Lemis Yavuz, Ruchi Jain, Khawla Abu Hammour, Ghalia F. Al-Hammouri, Maha El Naofal, Nour Halabi, Sawsan Yaslam, Sathishkumar Ramaswamy, Alan Taylor, Deena Wafadari, Ali Alsarhan, Hamda Khansaheb, Zulfa Omar Deesi, Rupa Murthy Varghese, Mohammed Uddin, Hanan Al Suwaidi, Suleiman Al-Hammadi, Abdulmajeed Alkhaja, Laila Mohamed AlDabal, Tom Loney, Norbert Nowotny, Abdulla Al Khayat, Alawi Alsheikh-Ali, Ahmad Abou Tayoun
Journal: JAMA Network Open (2022)

Clinical, genetic, and laboratory characteristics of Middle Eastern patients with multisystem inflammatory syndrome in children (MIS-C) have not yet been documented.To assess the genetic and clinical characteristics of patients with MIS-C of primarily Arab and Asian origin.A prospective, multicenter cohort study was conducted from September 1, 2020, to August 31, 2021, in the United Arab Emirates and Jordan. Forty-five patients with MIS-C and a matched control group of 25 healthy children with a confirmed SARS-CoV-2 infection status were recruited. Whole exome sequencing in all 70 participants was performed to identify rare, likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness.SARS-CoV-2.Fever, organ system complications, laboratory biomarkers, whole exome sequencing findings, treatments, and clinical outcomes were measured. The Mann-Whitney U test was used to assess the association between genetic variants and MIS-C attributes. The Fisher exact test was used to compute the genetic burden in MIS-C relative to controls.A total of 45 patients with MIS-C (23 [51.1%] male; 30 [66.7%] of Middle Eastern origin; mean [SD] age, 6.7 [3.6] years) and 25 controls (17 [68.0%] male; 24 [96.0%] of Middle Eastern origin; mean [SD] age 7.4 [4.0] years) participated in the study. Key inflammatory markers were significantly dysregulated in all patients with MIS-C. Mucocutaneous and gastrointestinal manifestations were each reported in 36 patients (80.0%; 95% CI, 66.1%-89.1%), cardiac findings were reported in 22 (48.9%; 95% CI, 35.0%-63.0%), and neurologic findings were reported in 14 (31.1%; 95% CI, 19.5%-45.6%). Rare, likely deleterious heterozygous variants in immune-related genes, including TLR3, TLR6, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%; 95% CI, 29.0%-56.7%), of whom 7 had multiple variants. There was higher enrichment of genetic variants in patients relative to controls (29 vs 3, P < .001). Patients with those variants tended to have earlier disease onset (7 patients [36.8%; 95% CI, 19.1%-58.9%] with genetic findings vs 2 [7.7%; 95% CI, 2.1%-24.1%] without genetic findings were younger than 3 years at onset) and resistance to treatment (8 patients [42.1%; 95% CI, 23.1%-63.7%] with genetic findings vs 3 patients [11.5%; 95% CI, 4.0%-29.0%] without genetic findings received 2 doses of intravenous immunoglobulin).The results of this cohort study suggest that rare, likely deleterious genetic variants may contribute to MIS-C disease. This finding paves the way for additional studies with larger, diverse populations to fully characterize the genetic contribution to this new disease entity.